Positive 2-year results with MD1003 in progressive MS

First drug capable of reversing disease progression in patients with progressive MS

Extension phase data demonstrate sustained efficacy up to 2 years

Both studies support efficacy specifically in patients with not-active progressive MS

Best effect size ever observed in this population

Good safety profile

PARIS- MedDay, a biotechnology company focused on the treatment of neurological diseases, today announces full study results from the MS-SPI and MS-ON trials, including the MS-SPI extension data, which will be presented at the 2016 American Academy of Neurology Annual Meeting today.

MS-SPI and MS-ON studies tested the efficacy of MD1003, a patented pharmaceutical-grade biotin administered at a dose of 300 mg per day in the treatment of multiple sclerosis (MS) and particularly of the most difficult to treat “not-active progressive MS,” for which there is no approved drug.

Overall these data show the best effect size ever observed to date and confirm the good safety profile of MD1003.

Commenting on the full study results, Prof. Ayman Tourbah, Principal Investigator of the studies, CHU de Reims, Department of Neurology, France, said:

Full results of the MS-SPI study are especially remarkable. This is the first time that a drug has reversed the progression of the disease in a statistically significant proportion of patients. In addition, if we look at the mean Expanded Disability Scale (EDSS) change, the data compare very favourably with all previous trials that looked at the same endpoint. Almost no progression was observed in patients treated with MD1003 for 24 months and this has never been observed before. When we compare these results to other trials in progressive MS that involved more than 6000 patients overall, this is clearly the best effect size ever observed. The MS-ON trial failed to reach its primary endpoint but this is most likely due to a majority of patients with relapsing remitting MS in this trial. Indeed if we focus on patients with the progressive chronic neuropathy phenotype, they seem to have benefited from the drug in the same way as patients in the MS-SPI trial. Results from both studies are therefore consistent and point to the fact that targeting neuron and oligodendrocyte metabolism represents a promising and novel disease modifying therapy approach in progressive MS, particularly in patients with a not-active progressive disease.

MS-SPI study results

The MS-SPI study was designed to assess the potential of MD1003 to reverse disease progression in patients with not-active progressive MS. Patients included in the study had to demonstrate disease progression of disability in the previous two years with no evidence of inflammatory activity. Patients were randomized to receive either MD1003 (n=103) or placebo (n=51) for 12 months, followed by a 12-month extension phase during which all patients received MD1003 but remained blinded as to whether they had received the active drug during the first phase. The primary endpoint was particularly challenging, and defined as the proportion of patients with either improvement of EDSS or TW25 (timed 25-foot walk) after nine months (M9) confirmed at 12 months (M12), which equates to a confirmed reversion of progression.

The primary endpoint was met (p=0.0051) with 12.6% of patients in the MD1003 arm showing a confirmed reversion of progression at M9 (confirmed at M12), compared to none (0%) in the placebo arm. During the 12-month extension phase, patients initially on MD1003 exhibited sustained improvement compared to baseline, with 13.2% of patients showing improvement at M18 (confirmed at M24) and 15.4% of patients showing improvement at M24. When patients in the placebo group were switched to MD1003 for the extension phase, the proportion of responders reached 7.1% at M18 (confirmed at M24) and 11.9% at M24, demonstrating that treatment with MD1003 reversed progression in some patients switched to MD1003.

The primary judgement criterion was supported by the mean change of EDSS from baseline in the overall population. The mean EDSS decreased between M0 and M12 in the MD1003 group (-0.03) compared to progression in the placebo group (+0.13, p=0.014). During the extension phase, the values remained relatively constant compared to baseline in patients maintained on MD1003 (from -0.03 to 0.04 at M24), indicating sustained efficacy, whereas patients initially on placebo stopped progressing on EDSS once switched to MD1003 (from +0.13 at M12 to +0.15 at M24, compared to baseline).

The efficacy demonstrated on EDSS was also supported by the mean clinical global impression of change scale (CGI) which was worse at M12 in the placebo group compared to the MD1003 group (p<0.0001). It remained constant in the extension phase for patients initially on MD1003 and improved after patients were switched from placebo to MD1003. As a result no difference was observed between the two groups at the end of the extension phase (p=0.92).

MS-ON study results

The MS-ON study was designed to investigate whether MD1003 could accelerate recovery following incomplete remission of an acute relapse and/or specifically improve patients with progressive disability. For this purpose, the study enrolled patients with fixed visual loss (≥6 months) following an acute optic neuritis in the previous three years (non-progressive chronic optic neuropathy, n=62) together with MS patients showing progressive visual loss assessed at two different visits in the previous three years (progressive optic neuropathy, n=31). The placebo-controlled phase was 24 weeks (65 patients received MD1003 and 28 received a placebo) followed by a 24-week extension phase during which all patients (n=92) received MD1003. The primary endpoint was the mean change from baseline in 100% contrast visual acuity (VA) at 24 weeks of the selected eye (defined as the eye with the worst visual acuity and acute or progressive worsening within the three years prior to inclusion).

Final results showed that, overall, patients who received MD1003 improved slightly more than patients who received the placebo (average of 3.1 letters in the MD1003 arm versus 1.8 letters in the placebo arm). However the difference did not reach statistical significance. Patients in both the MD1003 and placebo groups continued to improve during the extension phase (mean of 4.25 letters in the initial MD1003 arm versus 4.0 letters in the placebo arm switched to MD1003).

Prospectively defined subgroup analyses identified that only patients with progressive ON may benefit from MD1003, while no effect was observed in the largest subgroup of patients with non-progressive ON following a relapse. During the placebo-controlled phase, patients in the progressive chronic ON subgroup who received MD1003 improved by a mean of 2.75 letters, while patients who received the placebo worsened by a mean of -1.45 letters. During the 24-week extension phase, patients who were given MD1003 continued to improve (to a mean of 4.55 letters) while those who were initially on placebo stopped worsening after they were switched to the active drug (mean of -1.2 letters at 48 weeks).

Safety

Findings from both MS-SPI and MS-ON trials show that, overall, MD1003 is well tolerated. The incidence of adverse events was similar across the two groups in both studies. In some patients, abnormal laboratory data indicated that MD1003 could affect the results of immunoassays which use biotinylated antibodies and substrates.

Commenting on the full study results, Prof. Bruce Cree, UCSF, USA, principal investigator in the upcoming US study with MD1003, commented:

Taken together, these studies are very promising and provide hope for a condition that has thus far been largely intractable using treatments targeting neuro-inflammation. That the extension study from the SPI trial showed an apparent durability of effect suggests that high dose biotin may have disease modifying properties in addition to its proposed role in enhancing energy metabolism. Furthermore, the positive impact of high dose biotin points to a new line of inquiry in understanding the pathophysiology of progressive MS.

Ends

About progressive MS

MS is the most common disabling neurological disease among young adults, with first symptoms typically manifesting between 20 and 40 years of age. In the majority (85%) of cases, patients experience an initial phase of relapsing-remitting neurological dysfunction (RRMS), which typically evolves into a secondary progressive disease at a later point in the clinical course (SPMS). Once MS is in the progressive phase, individuals experience a gradual worsening of neurological disability. Primary progressive MS (PPMS) characterized by disease progression from onset affects 10–15% of MS patients. Progressive disease (either SPMS or PPMS) can be further divided into active or not-active progressive disease based on the existence or not of superimposed inflammatory activity. Immunosuppressive and immunomodulatory drugs have been shown to decrease the frequency of relapses and CNS lesions in relapsing remitting MS. These drugs may also delay progression in the subgroup of patients with active progressive MS. However, there is currently no drug targeting non-active progressive MS, which represents the larger and most difficult to treat population.

In relapsing MS, lymphocytes and monocytes of the peripheral adaptive immune system infiltrate perivascular brain and spinal cord tissue causing focal inflammation that can be identified on imaging as acute contrast enhancing lesions. The histopathological hallmark of these lesions is injury to oligodendroglia cells that wrap axons in myelin, the cell membrane that enhances electrical resistance and allows saltatory conduction through the nervous system. Axons themselves are typically relatively spared. In contrast, progressive MS is mainly associated with progressive axonal degeneration, chronic demyelination and, usually, little or no inflammation. It is considered that axonal degeneration results from energy failure caused by chronic demyelination and mitochondrial dysfunction.

About MD1003

MD1003 is a patented, highly dosed pharmaceutical grade biotin that has already shown efficacy in patients with progressive multiple sclerosis. MD1003 has a unique mode of action which potentially acts on two targets related to progressive MS: (1) it activates the Krebs cycle, the main route for energy production that protects against axonal degeneration and (2) it potentially activates acetyl-CoA carboxylases (ACC1 and ACC2), the rate-limiting enzymes in the synthesis of fatty acids required for myelin repair. The drug is already commercialized in some European countries under early-access programs.

About MedDay

MedDay is a privately held biotechnology company developing new drugs targeting brain metabolism for neurodegenerative diseases. The company was founded in 2011 by Frédéric Sedel, MD, PhD (Chief Executive Officer); and Guillaume Brion, MD (Chief Operating Officer). The Company’s most advanced pipeline candidate is MD1003 for the treatment of primary and secondary progressive multiple sclerosis. For more information, please see: www.medday-pharma.com.

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